S447X, a serine substitution by a stop codon on base 99 of exon 9 of the lipoprotein lipase (LPL) gene, has beneficial effects on blood lipids. Other LPL alleles are associated with lipid levels, but whether one of these variants predominates remains elusive. We performed a systematic survey to identify single-nucleotide polymorphisms (SNPs) in all 10 LPL exons and flanking regions by resequencing the gene in 95 subjects. Of 24 variants, 14 were common (≥3%). We assayed the common SNPs in 186 cases with atherogenic lipid profiles (low HDL, high LDL) and 185 nonatherogenic controls (high HDL, low LDL). Only S447X and exons 6 (base +73) and 10 (base −11) were individually associated with case-control status (P<0.05, adjusted for major nongenetic covariates with known lipid effects). There were no significant SNP×gender interactions. In adjusted multi-SNP and haplotypic analyses, S447X was interpretable as the sole predictor, with a 2–3-fold reduction in the odds of being atherogenic vs. nonatherogenic (adjusted OR, 0.39; 95% CI, 0.21–0.73). S447X and base −11 of exon 10 were statistically interchangeable because they are strongly associated (r=0.92, P<0.0001), but we posit that the LPL association with lipid profile is more likely attributable to the functional S447X rather than the nonfunctional exon 10 SNP. It appears that the S447X variant of LPL may be another rare example (like APOE4, factor V-Leiden, and PPARγ Pro12Ala) of a common variant predisposing to a common disorder. Genet Epidemiol 24:309–321, 2003. © 2003 Wiley-Liss, Inc.